PROJECT SUMMARY Chronic kidney disease (CKD) is associated with neurocognitive dysfunction in children and young adults, including deficits in attention, memory, and executive function, which can have far-reaching and lifelong adverse consequences. The specific pathophysiologic mechanisms leading to neurocognitive impairment in CKD remain unknown, but metabolic alterations caused by uremic toxins are thought to have a significant impact on cognitive function. Metabolomics offers a novel method to elucidate the neuropathological role of a broad range of uremic toxins. Recent advances in metabolomic technologies allow for high-throughput, high-resolution metabolic phenotyping of small volume human blood samples that offers great promise for the discovery of highly discriminant biomarkers of diseases and their consequences. Discovery of specific metabolic profiles that associate with neurocognitive dysfunction in CKD is critical to understanding pathophysiologic mechanisms and to informing targeted therapeutic approaches. The primary purpose of this study is to discover novel metabolites associated with neurocognitive dysfunction in children and young adults with CKD, by analyzing blood metabolomic profiles of participants in two large cohorts: the Chronic Kidney Disease in Children (CKiD) and the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) studies. These two cohort studies are unique in their comprehensive neurocognitive phenotyping and have contributed to the majority of current understanding of neurocognitive dysfunction in childhood CKD. The proposed project will utilize a state-of-the-art non-targeted platform for global metabolomic profiling and leverage the robust neurocognitive data and biorepository samples of the CKiD and NiCK cohorts to perform the first large-scale discovery of biomarkers of neurocognitive impairment in children and young adults with CKD. The association of blood metabolites with age-normalized Z scores for measures of intellectual functioning, attention regulation, working memory, and executive function will be examined in >500 children in CKiD and in 65 children and young adults with CKD compared to 67 healthy controls in NiCK, frequency-matched on age, sex, race and socioeconomic status.